Transcriptomic Remodelling of Fetal Endothelial Cells During Establishment of Inflammatory Memory.

Inflammatory memory involves the molecular and cellular 'reprogramming' of innate immune cells following exogenous stimuli, leading to non-specific protection against subsequent pathogen exposure. This phenomenon has now also been described in non-hematopoietic cells, such as human fetal and adult endothelial cells. In this study we mapped the cell-specific DNA methylation profile and the transcriptomic remodelling during the establishment of inflammatory memory in two distinct fetal endothelial cell types - a progenitor cell (ECFC) and a differentiated cell (HUVEC) population. We show that both cell types have a core transcriptional response to an initial exposure to a viral-like ligand, Poly(I:C), characterised by interferon responsive genes. There was also an ECFC specific response, marked by the transcription factor ELF1, suggesting a non-canonical viral response pathway in progenitor endothelial cells. Next, we show that both ECFCs and HUVECs establish memory in response to an initial viral exposure, resulting in an altered subsequent response to lipopolysaccharide. While the capacity to train or tolerize the induction of specific sets of genes was similar between the two cell types, the progenitor ECFCs show a higher capacity to establish memory. Among tolerized cellular pathways are those involved in endothelial barrier establishment and leukocyte migration, both important for regulating systemic immune-endothelial cell interactions. These findings suggest that the capacity for inflammatory memory may be a common trait across different endothelial cell types but also indicate that the specific downstream targets may vary by developmental stage.

Population-based analysis of sociodemographic predictors, health-related quality of life and health service use associated with obstructive sleep apnoea and insomnia in Australia.

Although there is growing recognition of the effects of living with sleep disorders and the important role of primary care in their identification and management, studies indicate that the detection of sleep apnoea (OSA) and insomnia may still be low. This large representative community-based study (n=2977 adults) used logistic regression models to examine predictors of self-reported OSA and current insomnia and linear regression models to examine the association of these sleep conditions with both mental and physical components of health-related quality of life (HRQoL) and health service use. Overall, 5.6% (95% confidence interval (CI) 4.6-6.7) and 6.8% (95% CI 5.7-7.9) of subjects self-reported OSA (using a single-item question) and current insomnia (using two single-item questions) respectively. Many sociodemographic and lifestyle predictors for OSA and insomnia acted in different directions or showed different magnitudes of association. Both disorders had a similar adverse relationship with physical HRQoL, whereas mental HRQoL was more impaired among those with insomnia. Frequent consultations with a doctor were associated with a lower physical HRQoL across these sleep conditions; however, lower mental HRQoL among those frequently visiting a doctor was observed only among individuals with insomnia. The adverse relationship between sleep disorders and physical and mental HRQoL was substantial and should not be underestimated.

Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk.

BACKGROUND: Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual's susceptibility to age-related diseases such as CRC. METHODS: We conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual's chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk. RESULTS: Each epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10-30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group. CONCLUSIONS: Among the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigenetic aging process.

DNA methylation changes following DNA damage in prostate cancer cells.

Many cancer therapies operate by inducing double-strand breaks (DSBs) in cancer cells, however treatment-resistant cells rapidly initiate mechanisms to repair damage enabling survival. While the DNA repair mechanisms responsible for cancer cell survival following DNA damaging treatments are becoming better understood, less is known about the role of the epigenome in this process. Using prostate cancer cell lines with differing sensitivities to radiation treatment, we analysed the DNA methylation profiles prior to and following a single dose of radiotherapy (RT) using the Illumina Infinium HumanMethylation450 BeadChip platform. DSB formation and repair, in the absence and presence of the DNA hypomethylating agent, 5-azacytidine (5-AzaC), were also investigated using γH2A.X immunofluorescence staining. Here we demonstrate that DNA methylation is generally stable following a single dose of RT; however, a small number of CpG sites are stably altered up to 14 d following exposure. While the radioresistant and radiosensitive cells displayed distinct basal DNA methylation profiles, their susceptibility to DNA damage appeared similar demonstrating that basal DNA methylation has a limited influence on DSB induction at the regions examined. Recovery from DSB induction was also similar between these cells. Treatment with 5-AzaC did not sensitize resistant cells to DNA damage, but rather delayed recruitment of phosphorylated BRCA1 (S1423) and repair of DSBs. These results highlight that stable epigenetic changes are possible following a single dose of RT and may have significant clinical implications for cancer treatment involving recurrent or fractionated dosing regimens.

Older People Who Are Frequent Users of Acute Care: A Symptom of Fragmented Care? A Case Series Report on Patients' Pathways of Care.

Older frequent users of acute care can experience fragmented care. There is a need to understand the issues in a local context before attempting to address fragmented care. 0.5% (n=61) of the population in a defined local government area were identified as having ≥4 unplanned emergency department (ED) presentations/ admissions to an acute-care hospital over 13 months. A retrospective case-series study was conducted to examine detailed pathways of care for 17 patients within the identified population. The two dominant presentation reasons were clinical symptoms associated with a declining/significant loss of capacity in fundamental self-care activities and chronic cardiac/respiratory conditions. Of patients discharged home, 21% of discharge letters were delayed >7 days and only 19% received a written discharge plan. Half of community dwelling patients received home nursing and/or assistance. Frequent users of acute care can experience untimely hospital communication and may require more coordinated care provided in the community to assist self-care and manage chronic conditions.

Emotional labour and aboriginal maternal infant care workers: The invisible load.

BACKGROUND: The term 'emotional labour' has been used to describe the competing demands on midwives to empathize with clients whilst maintaining a level of professional detachment. Previous research indicates that when individuals experience difficulty managing these emotions, burnout may result. Aboriginal health care workers often have roles with large emotional demands, as they are relied upon heavily to engage clients in care. However, the concept of emotional labour has received little attention in relation to this group. AIM: To explore potential sources of emotional labour for Aboriginal Maternal Infant Care workers in a maternity care program for Aboriginal women in South Australia. The program involves these workers providing care for women in partnership with midwives. METHODS: We employed a phenomenological approach. Thirty in-depth interviews were conducted with staff and clients of the program. Recorded interviews were transcribed and coded and emerging themes identified. FINDINGS: This workforce undertakes extensive emotional labour. Key sources include the cultural and family obligations they have to clients, complex social needs of many clients, and potential for community backlash when poor perinatal outcomes occur. A lack of respect for the role within the workplace further contributes to these experiences. CONCLUSION: This study found that the responsibilities inherent to the role as both cultural broker and carer create significant emotional labour for workers. Recommendations to address this and enhance the sustainability of this workforce include: recognition and valuing of emotional work by management and other staff, enhancing cultural awareness training, and building stress-relieving activities into the workplace.

Management of Musculoskeletal Conditions in Rural South Australia: A Randomised Controlled Trial.

With age, the prevalence of musculoskeletal conditions increases markedly. This rural-based study determined the benefits of two approaches for managing musculoskeletal conditions: a multiple-component 'Self-management Plus' intervention, and usual care. The intervention combined self-management education with physical activity and health professional support. 6-month outcomes included: Clinical Global Impression-Improvement Scale (CGI-IS) and Quality of Life (QoL). A total of 145 people were recruited; mean (SD) age was 66.1 (11.1) and 63.3 (10.9) years for intervention and control groups respectively. The intervention resulted in greater improvements in global functioning (CGI-IS mean (SD) = 3.2 (1.3)) than usual care (CGI-IS mean (SD) = 4.2 (1.5)). There was no difference in QoL improvement between study groups. A multiple-component 'Self-management Plus' intervention had a positive effect on physical functioning for older adults with musculoskeletal conditions. However, recruitment and retention of participants was problematic, which raises questions about the intervention's feasibility in its current form.

Expression discordance of monozygotic twins at birth: effect of intrauterine environment and a possible mechanism for fetal programming.

Within-pair comparison of monozygotic (MZ) twins provides an ideal model for studying factors that regulate epigenetic profile, by controlling for genetic variation. Previous reports have demonstrated epigenetic variability within MZ pairs, but the contribution of early life exposures to this variation remains unclear. As epigenetic marks govern gene expression, we have used gene expression discordance as a proxy measure of epigenetic discordance in MZ twins at birth in two cell types. We found strong evidence of expression discordance at birth in both cell types and some evidence for higher discordance in twin pairs with separate placentas. Genes previously defined as being involved in response to the external environment showed the most variable expression within pairs, independent of cell type, supporting the idea that even slight differences in intrauterine environment can influence expression profile. Focusing on birthweight, previously identified as a predisposing factor for cardiovascular, metabolic and other complex diseases, and using a statistical model that estimated association based on within-pair variation of expression and birthweight, we found some association between birthweight and expression of genes involved in metabolism and cardiovascular function. This study is the first to examine expression discordance in newborn twins. It provides evidence of a link between birthweight and activity of specific cellular pathways and, as evidence points to gene expression profiles being maintained through cell division by epigenetic factors, provides a plausible biological mechanism for the previously described link between low birthweight and increased risk of later complex disease.

A psycho-behavioral model of genital herpes recurrence.

To develop a model of how stress and other psychosocial constructs may interact to explain recurrences of genital herpes, assessments of major and minor life stress, locus of control, arousal or stimulation seeking, and social support were given to 153 university students (33% male; 67% female) who were seropositive for genital herpes. Retrospective and concurrent indices of illness vulnerability were evaluated. Serum levels of thymosin-alpha-1, a peptide sensitive to psychosocial stress, were measured at the beginning of the study. A causal model suggested by previous research was not supported by the data. An alternate model showed that psychosocial stress did not affect herpes recurrence directly, but instead predisposed subjects to more generalized illnesses, which in turn mediated recurrences. Social support increased rather than decreased the likelihood of illness vulnerability, thus increasing the risk of recurrence. Higher levels of both arousal seeking and external locus of control increased illness vulnerability but moderated the likelihood of herpes recurrence. Higher levels of thymosin-alpha-1 were related to greater illness vulnerability but this peptide was not associated with psychosocial stress as originally predicted. Additional construct validation of the role of illness vulnerability in increasing the risk of herpes recurrence is recommended.

Daily stress and recurrence of genital herpes simplex.

It is widely believed that emotional stress triggers recurrences of both oral and genital herpes simplex virus. On a daily basis, we studied 64 subjects prospectively for 1 to 3 months; all subjects had at least one culture-proved recurrence of genital herpes simplex virus type 2 before or during the study. All subjects filled out a questionnaire that measured psychological/emotional stress in six areas: physical health, relations with friends, relations with family, relations with sex partner(s), financial, and vocation/education. These questionnaires were mailed back to us daily. Data were analyzed by General Linear Models analysis of variance to compare stress reported on each of the 6 days before a recurrence with that on days during or after a recurrence, as well as days not temporally related to recurrence. Under these conditions, in which retrospective bias was minimized, there was no significant increase in psychological/emotional stress on any day in any area preceding a recurrence of genital herpes simplex virus.

Game playing: a way to look at nursing models.

This paper deals with macrotheories of nursing and a new way of looking at them. It also shows through the use of a board game why the discipline of nursing would be greatly hindered in its development by the acceptance of only one of the nursing macrotheories available today. The board game shows that macrotheorists of nursing do not discuss death and dying as a part of their conceptual models. Since death is not incorporated into the concepts, then they are not describing or explaining all the aspects dealt with in the discipline of nursing. This is not to say that theory is not necessary but that the acceptance of only one nursing macrotheory (model) is limiting and inhibiting. It denies nursing the ability to create and use intuition.

Biofeedback-assisted sexual arousal in females: a comparison of visual and auditory modalities.

This study was undertaken to investigate the effects of instructional set and biofeedback modality upon the ability of 23 females to achieve control over sexual arousal. Two levels of instructional set (increase, decrease) were completely crossed with three feedback modalities (audio, visual, no feedback). Changes in vaginal blood volume (VBV) and vaginal pulse amplitude (VPA) were monitored by a vaginal plethysmograph and reduced on line by a microcomputer. During feedback trials, all subjects received audio- or visual feedback of the VBV response. Subjects participated in two sessions, each consisting of six 3-minute trials, one in each instruction/feedback combination. Order of trials was counterbalanced. Subjective levels of arousal, VBV, and VPA were significantly higher under increase instructions. Also, a significant feedback effect was noted in the subjective measure and the VBV measure, favoring visual feedback for overall control of sexual arousal. However, the feedback effect accounted for a small portion of the variance, and it was concluded that performance was not appreciably superior with or without feedback. Thus practical considerations may determine the feedback modality to be used for vaginal vasocongestion in future research. Higher positive correlations of subjective ratings with vaginal blood volume occurred during feedback trials, which suggests that biofeedback may be helpful in discrimination training to facilitate awareness of the feelings associated with different arousal levels and correct labeling of increased vasocongestion as sexual. Further research is necessary to see if sexually dysfunctional women can benefit from a biofeedback component in a comprehensive therapy program and to determine the effect of many training sessions on discrimination and self-control of arousal.

Styles of sexual expression in women: clinical implications of multivaritanalyses.

Two different multivariate techniques were applied to self-reported trait and behavioral data concerning sexual behavior from a sample of North American women. Canonical correlation delineated three styles in which certain demographic attributes and cognitive indices of sexual arousal were related to forms of sexual expression. The first style was characterized by respondents who experienced high rates of intercourse and orgasm in a cohabitation arrangement but who did not necessarily report satisfaction with their sexual responsivity. A second style was characterized by older women currently without partners who expressed a liking for erotic literature and media, direct genital stimulation, and frequent masturbation but who were dissatisfied with their sexual responsivity. The third style, which included respondents most satisfied with their sexual responsivity, was characterized by women who were more aware of physiological changes during sexual arousal and who enjoyed gently seductive erotic activities, breast stimulation, and genital stimulation. A discriminant analysis showed that those women who were most highly satisfied with their sexual responsivity experienced frequent intercourse and orgasm consistency, enjoyed gently seductive erotic activities and breast stimulation, but were unresponsive to erotic literature and media. A second discriminant analysis showed that women who achieved orgasm most consistently were older, were more aware of physiological changes during sexual arousal, reported higher frequencies of masturbation and intercourse, and were less likely to be aroused by erotic preliminaries. These results are discussed within the context of the literature on the treatment and prevention of sexual dysfunction.

Sexual arousal in women: a comparison of cognitive and physiological responses by continuous measurement.

Six sexually normal women were exposed to a wide variety of erotic video tapes while vaginal, groin, and breast vasocongestion measures were tkane. The women indicated their level of sexual arousal while viewing the tapes by positioning a lever device along a calibrated scale. The results indicated highly significant positive correlations among the cognitive and physiological measures for five out of six individual subjects, although the pooled group data failed to show significance. The methodology described in this research shows promise as a diagnostic and research tool.

An inventory for the measurement of female sexual arousability: the SAI.

This report describes the development of a self-report Sexual Arousability Inventory (SAI) for women. Sexual arousability was defined as the sum of a respondent's ratings of 28 erotic experience along a 7-point Likert arousal dimension. Multiple-regression and factor analyses were used to select valid items from a 131-item pool and build in factorial purity. The SAI has concurrent validity with respect to sexual experience, activity, and satisfaction, and discriminates between clinical and normal populations. In addition, the SAI is easy to administer and score, may be used with single, married, or lesbian women, is available with norms and in alternate forms, and possesses exceptional internal consistency. Although the SAI was designed primarily for clinical use, the construct it measures may have theoretical significance in future research.